Clinical trials are actively evaluating cancer treatments as outlined below: 1.) Isolated organ perfusion of the liver using melphalan and hyperthermia. Isolated hepatic perfusion (IHP) has resulted in substantial and durable regression of locally advanced cancers in the majority of patients treated. In patients with advanced unresectable liver cancers, IHP with TNF and melphalan resulted in significant regression of tumors (> 50% reduction in size) in 75% of patients. Tumor responses are seen in all histologies treated and occur even in patients with large (>10 cm) lesions, multiple tumors, or those with a significant (>30%) tumor burden in liver. An overall responses rate of 70% was obtained in patients with ocular melanoma metastatic to liver with a median duration of almost 12 months. Recently, patients with colorectal metastases to liver were treated with a combination of IHP and melphalan followed by hepatic artery infusion of floxuridine and leucovorin. An overall response rate of 74% with a median duration of response of 18 months and an overall median survival of 27 months were obtained. Currently, a random assignment trial is being conducted for patients with unresectable colorectal cancers to liver comparing initial IHP with melphalan to no IHP. All patients subsequently receive 6 to 12 months of hepatic artery infusion of FUDR and systemic combination chemotherapy. 2.) A trial evaluating the use of radiofrequency ablation (RFA) for local ablation of hepatic tumors is being conducted. RFA has been shown in preliminary results to be an effective modality for local control of tumors up to 6 cm in diameter. 3.) A random assignment trial evaluating disease-free and overall survival for patients undergoing resection of colorectal metastases (except for bone or brain) followed by adjuvant oral thalidomide versus placebo. 4.) A clinical trial using PET scan with new radiopharmaceuticals to quantify changes in tumor viability, metabolism, and blood flow in patients treated with antiangiogenic therapies. Initial results indicate that PET scan is a very sensitive test for detecting occult tumors and may provide valuable insights into the efficacy and mechanisms of action of antiangiogenic therapies. 5.) A clinical trial of aggressive tumor debulking and continuous hyperthermic peritoneal perfusion (CHPP) is being conducted for patients with carcinomatosis from GI malignancies or mesothelioma. Post-operative intraperitoneal 5-FU and paclitaxel are adminsitered as a dwell on day 7 after surgery. Laboratory research falls into several broad areas that complement and advance the clinical research effort. In order to better understand the mechanisms of antitumor activity in isolated organ perfusion, we have been characterizng the effects of melphalan, hyperthermia, and TNF on endothelial tissue in vitro and on tumor microvasculature in experimental animal models and in patients undergoing isolation perfusion. The unique phenotype of tumor neovasculature is thought to represent the major element through which the antitumor effects of isolation perfusion are mediated. Data show that there is a marked and selective increase in permeability and procoagulant activity in endothelial tissue in culture and in tumor neovasculature during isolation perfusion secondary to hyperthermia. These effects are thought to result in augmented delivery and retention of chemotherapy directly in tumor. We have shown that tumors confer a unique phenotype on adjacent endothelial tissue that may render it sensitive to the effects of hyperthermia or TNF. Currently, we are using micorarray of tumor samples obtained during isolation perfusion to profile the activated cellular pathways that are associated with tumor regression following isolation perfusion which may provide insights on mechanisms that can be exploited to improve results of therapy. Overall, the goal of these studies is to refine the development isolation perfusion as a treatment option for patients with regionally advanced cancers.